Simultaneous isolation of intact brain cells and cell-specific extracellular vesicles from cryopreserved Alzheimer's disease cortex.

BACKGROUND: The neuronal and gliaI populations within the brain are tightly interwoven, making isolation and study of large populations of a single cell type from brain tissue a major technical challenge. Concurrently, cell-type specific extracellular vesicles (EVs) hold enormous diagnostic and therapeutic potential in neurodegenerative disorders including Alzheimer's disease (AD). NEW METHOD: Postmortem AD cortical samples were thawed and gently dissociated. Following filtration, myelin and red blood cell removal, cell pellets were immunolabeled with fluorescent antibodies and analyzed by flow cytometry. The cell pellet supernatant was applied to a triple sucrose cushion for brain EV isolation. RESULTS: Neuronal, astrocyte and microglial cell populations were identified. Cell integrity was demonstrated using calcein AM, which is retained by cells with esterase activity and an intact membrane. For some experiments cell pellets were fixed, permeabilized, and immunolabeled for cell-specific markers. Characterization of brain small EV fractions showed the expected size, depletion of EV negative markers, and enrichment in positive and cell-type specific markers. COMPARISON WITH EXISTING METHODS AND CONCLUSIONS: We optimized and integrated established protocols, aiming to maximize information obtained from each human autopsy brain sample. The uniqueness of our method lies in its capability to isolate cells and EVs from a single cryopreserved brain sample. Our results not only demonstrate the feasibility of isolating specific brain cell subpopulations for RNA-seq but also validate these subpopulations at the protein level. The accelerated study of EVs from human samples is crucial for a better understanding of their contribution to neuron/glial crosstalk and disease progression.

Neuropathologic changes at age 90+ related to sleep duration 19 to 40 years earlier: The 90+ Study.

INTRODUCTION: We investigated the association between sleep duration and neuropathologic changes 19 to 40 years later in oldest-old (age 90+) participants of The 90+ Study. METHODS: Participants self-reported sleep duration and underwent neuropathologic evaluation. We categorized sleep duration as < 7, 7 to 8 = reference, > 8 hours and dichotomized neuropathologic changes as present/absent. We estimated odds ratio (OR) and 95% confidence intervals (CI) using logistic regression. RESULTS: In 264 participants, mean age at sleep self-report was 69 years, mean age at autopsy was 98 years, and mean interval between sleep self-report and autopsy was 29 years (range: 19-40). Those reporting > 8 hours of sleep had lower likelihood of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) inclusions (OR = 0.18; CI = 0.04-0.82) and amyloid beta deposits (OR = 0.34; 95% CI = 0.12-0.94). DISCUSSION: Long self-reported sleep is associated with lower odds of neurodegenerative neuropathologic changes 19 to 40 years later in the oldest-old, suggesting a potential role of sleep in accumulation of dementia-related neuropathologies. HIGHLIGHTS: Association of self-reported sleep with non-Alzheimer's disease neuropathologic changes has not been explored. Whether sleep duration is related to dementia neuropathologic changes decades later is unclear. Long self-reported sleep is associated with lower odds of Alzheimer's disease neuropathologic change 19 to 40 years later in the oldest-old. Long self-reported sleep is associated with lower odds of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change 19 to 40 years later in the oldest-old.

The Relationship between All-Cause Dementia and Acute Diabetes Complications among American Indian and Alaska Native Peoples.

BACKGROUND: American Indian and Alaska Native people (AI/AN) bear a disproportionate burden of diabetes. Growing evidence shows significant associations between several acute diabetes complications and dementia among diabetes patients. However, little is known about these relationships among AI/AN adults. Here, we aim to investigate these associations among AI/AN adults. METHODS: This cross-sectional study extracted data from the Indian Health Service's (IHS) National Data Warehouse and related administrative databases. A total of 29,337 IHS actual users with diabetes who were 45+ years old during fiscal year 2013 were included. All-cause dementia and diabetes complications were identified using ICD-9 diagnostic codes. Negative binomial regression models were used to evaluate the associations of interest. RESULTS: Nearly 3% of AI/AN diabetes patients had a dementia diagnosis. After controlling for covariates, dementia was associated with a 94% higher rate of severe hypoglycemia (Incidence Rate Ratio [IRR = 1.94, 95% CI:1.50-2.51), 52% higher rate of severe hyperglycemia (IRR = 1.52, 95% CI, 1.11-2.08), and 92% higher rate of any acute complication (IRR = 1.92, 95% CI:1.53-2.41). CONCLUSIONS: AI/AN diabetes patients with dementia suffered from considerably higher rates of acute diabetes complications than their counterparts without dementia. The clinical management of patients with comorbid diabetes and dementia is particularly challenging and may require individualized treatment approaches.

Racial and ethnic differences in the association between depressive symptoms and cognitive outcomes in older adults: Findings from KHANDLE and STAR.

INTRODUCTION: Depressive symptoms are associated with higher risk of dementia, but how they impact cognition in diverse populations is unclear. METHODS: Asian, Black, Latino, or White participants (n = 2227) in the Kaiser Healthy Aging and Diverse Life Experiences (age 65+) and the Study of Healthy Aging in African Americans (age 50+) underwent up to three waves of cognitive assessments over 4 years. Multilevel models stratified by race/ethnicity were used to examine whether depressive symptoms were associated with cognition or cognitive decline and whether associations differed by race/ethnicity. RESULTS: Higher depressive symptoms were associated with lower baseline verbal episodic memory scores (-0.06, 95% CI: -0.12, -0.01; -0.15, 95% CI: -0.25, -0.04), and faster decline annually in semantic memory (-0.04, 95% CI: -0.07, -0.01; -0.10, 95% CI: -0.15, -0.05) for Black and Latino participants. Depressive symptoms were associated with lower baseline but not decline in executive function. DISCUSSION: Depressive symptoms were associated with worse cognitive outcomes, with some evidence of heterogeneity across racial/ethnic groups. HIGHLIGHTS: We examined whether baseline depressive symptoms were differentially associated with domain-specific cognition or cognitive decline by race/ethnicity. Depressive symptoms were associated with worse cognitive scores for all racial/ethnic groups across different domains examined. Higher depressive symptoms were associated with faster cognitive decline for semantic memory for Black and Latino participants. The results suggest a particularly harmful association between depressive symptoms and cognition in certain racial/ethnic groups.

Potential Effects of Long-Term Exposure to Air Pollution on Dementia: A Longitudinal Analysis in American Indians Aged 55 Years and Older.

(1) Background: American Indians are disproportionately affected by air pollution, an important risk factor for dementia. However, few studies have investigated the effects of air pollution on the risk of dementia among American Indians. (2) Methods: This retrospective cohort study included a total of 26,871 American Indians who were 55+ years old in 2007, with an average follow-up of 3.67 years. County-level average air pollution data were downloaded from land-use regression models. All-cause dementia was identified using ICD-9 diagnostic codes from the Indian Health Service's (IHS) National Data Warehouse and related administrative databases. Cox models were employed to examine the association of air pollution with dementia incidence, adjusting for co-exposures and potential confounders. (3) Results: The average PM2.5 levels in the IHS counties were lower than those in all US counties, while the mean O3 levels in the IHS counties were higher than the US counties. Multivariable Cox regressions revealed a positive association between dementia and county-level O3 with a hazard ratio of 1.24 (95% CI: 1.02-1.50) per 1 ppb standardized O3. PM2.5 and NO2 were not associated with dementia risk after adjusting for all covariates. (4) Conclusions: O3 is associated with a higher risk of dementia among American Indians.

Neuropathologic Burden and Dementia in Nonagenarians and Centenarians: Comparison of 2 Community-Based Cohorts

BACKGROUND AND OBJECTIVES: The aim of this study was to compare 2 large clinicopathologic cohorts of participants aged 90+ and to determine whether the association between neuropathologic burden and dementia in these older groups differs substantially from those seen in younger-old adults. METHODS: Autopsied participants from The 90+ Study and Adult Changes in Thought (ACT) Study community-based cohort studies were evaluated for dementia-associated neuropathologic changes. Associations between neuropathologic variables and dementia were assessed using logistic or linear regression, and the weighted population attributable fraction (PAF) per type of neuropathologic change was estimated. RESULTS: The 90+ Study participants (n = 414) were older (mean age at death = 97.7 years) and had higher amyloid/tau burden than ACT <90 (n = 418) (mean age at death = 83.5 years) and ACT 90+ (n = 401) (mean age at death = 94.2 years) participants. The ACT 90+ cohort had significantly higher rates of limbic-predominant age-related TDP-43 encephalopathy (LATE-NC), microvascular brain injury (µVBI), and total neuropathologic burden. Independent associations between individual neuropathologic lesions and odds of dementia were similar between all 3 groups, with the exception of µVBI, which was associated with increased dementia risk in the ACT <90 group only (odds ratio 1.5, 95% CI 1.2-1.8, p < 0.001). Weighted PAF scores indicated that eliminating µVBI, although more prevalent in ACT 90+ participants, would have little effect on dementia. Conversely, eliminating µVBI in ACT <90 could theoretically reduce dementia at a similar rate to that of AD neuropathologic change (weighted PAF = 6.1%, 95% CI 3.8-8.4, p = 0.001). Furthermore, reducing LATE-NC in The 90+ Study could potentially reduce dementia to a greater degree (weighted PAF = 5.1%, 95% CI 3.0-7.3, p = 0.001) than either ACT cohort (weighted PAFs = 1.69, 95% CI 0.4-2.7). DISCUSSION: Our results suggest that specific neuropathologic features may differ in their effect on dementia among nonagenarians and centenarians from cohorts with different selection criteria and study design. Furthermore, microvascular lesions seem to have a more significant effect on dementia in younger compared with older participants. The results from this study demonstrate that different populations may require distinct dementia interventions, underscoring the need for disease-specific biomarkers.

Characterizing Limbic-Predominant Age-Related TDP-43 Encephalopathy Without Alzheimer's Disease and Lewy Body Dementia in the Oldest Old: A Case Series.

BACKGROUND: Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a clinicopathological construct proposed to facilitate studying TDP-43 pathology in older individuals. OBJECTIVE: Our aim was to describe clinical and cognitive characteristics of LATE-NC without Alzheimer's disease neuropathologic change (ADNC) and Lewy body (LB) and to compare this with ADNC and primary age related tauopathy (PART). METHODS: In 364 autopsies of the oldest old of The 90+ Study, we identified those with LATE-NC without ADNC and LB. Control groups were participants with ADNC and PART. RESULTS: Of 31% of participants who had LATE-NC, only 5 (1.4%) had LATE-NC without ADNC and LB, all of whom had tau. These participants had a gradual and progressive cognitive decline. Four (80%) had dementia at death, a rate that was higher than ADNC (50%) and PART (21.7%). Mean duration of cognitive impairment was twice as long in LATE-NC without ADNC and LB (6.2 years) compared to ADNC (2.9 years) and PART (3 years). LATE-NC without ADNC and LB group had a higher prevalence of syncope, depression, and extrapyramidal signs than the ADNC and PART groups. CONCLUSIONS: Despite the high prevalence of LATE-NC, LATE-NC without ADNC and LB was rare in this large oldest-old cohort, highlighting the very high prevalence of multiple pathologic changes in the oldest old. Slowly progressive cognitive decline, ubiquitous memory impairment, history of syncope and depression, and extrapyramidal signs were prominent features among our LATE-NC without ADNC and LB group.

Racial and Ethnic Differences in the Association between Depressive Symptoms and Cognitive Outcomes in Older Adults: Findings from KHANDLE and STAR.

INTRODUCTION: Depressive symptoms are associated with higher risk of dementia but how they impact cognition in diverse populations is unclear. METHODS: Asian, Black, LatinX, or White participants (n=2,227) in the Kaiser Healthy Aging and Diverse Life Experiences (age 65+) and the Study of Healthy Aging in African Americans (age 50+) underwent up to three waves of cognitive assessments over four years. Multilevel models stratified by race/ethnicity were used to examine whether depressive symptoms were associated with cognition or cognitive decline and whether associations differed by race/ethnicity. RESULTS: Higher depressive symptoms were associated with lower baseline verbal episodic memory scores (-0.06, 95%CI: -0.12, -0.01; -0.15, 95%CI: -0.25, -0.04), and faster decline annually in semantic memory (-0.04, 95%CI: -0.07, -0.01; -0.10, 95%CI: -0.15, -0.05) for Black and LatinX participants. Depressive symptoms were associated with lower baseline but not decline in executive function. DISCUSSION: Depressive symptoms were associated with worse cognitive domains, with some evidence of heterogeneity across racial/ethnic groups.

Self-reported sleep in relation to risk of dementia a quarter of a century later at age 90+: The 90+ Study.

OBJECTIVE: To examine sex-specific associations of sleep duration and napping self-reported at mean age of 69 years (range: 53-81) with risk of incident dementia 24 years later at age 90 +. METHOD: Analytic sample included individuals from a population-based study who reported sleep and napping once in the 1980s and 24 years later (range: 16-38) joined The 90+ Study and were evaluated in-person. Those without dementia at baseline of The 90+ Study were prospectively followed. Hazard ratios [HR] and 95% confidence intervals [CI] of dementia risk were estimated by Cox regression. RESULTS: Of 574 participants 71% were women, mean age at start of dementia follow-up with The 90+ Study was 93 years (range: 90-102). After 3.3 years (range: 0.4-13.8) of follow-up 47% developed dementia. Higher risk of dementia at age 90+ was seen in women with <6 hours of self-reported sleep per night (adjusted HR = 2.00; 95% CI = 1.15-3.50; p = .01) compared with 8 hours. Lower risk of dementia at 90+ was seen in men with short-to-moderate (<60 minutes) self-reported naps compared with no naps (HR = 0.33; 95% CI = 0.18-0.63; p < .01). CONCLUSIONS: Sleep and nap 24 years earlier are important risk factors for dementia after age 90.

Spatial proteomics reveals human microglial states shaped by anatomy and neuropathology.

Microglia are implicated in aging, neurodegeneration, and Alzheimer's disease (AD). Traditional, low-plex, imaging methods fall short of capturing in situ cellular states and interactions in the human brain. We utilized Multiplexed Ion Beam Imaging (MIBI) and data-driven analysis to spatially map proteomic cellular states and niches in healthy human brain, identifying a spectrum of microglial profiles, called the microglial state continuum (MSC). The MSC ranged from senescent-like to active proteomic states that were skewed across large brain regions and compartmentalized locally according to their immediate microenvironment. While more active microglial states were proximal to amyloid plaques, globally, microglia significantly shifted towards a, presumably, dysfunctional low MSC in the AD hippocampus, as confirmed in an independent cohort (n=26). This provides an in situ single cell framework for mapping human microglial states along a continuous, shifting existence that is differentially enriched between healthy brain regions and disease, reinforcing differential microglial functions overall.

Neuropathologic Changes of Alzheimer's Disease and Related Dementias: Relevance to Future Prevention.

BACKGROUND: Decedents with late-life dementia are often found at autopsy to have vascular pathology, cortical Lewy bodies, hippocampal sclerosis, and/or TDP-43 encephalopathy alone or with concurrent Alzheimer's disease (AD) lesions. Nonetheless, it is commonly believed that AD neuropathologic changes (NC) are the dominant or exclusive drivers of late-life dementia. OBJECTIVE: Assess associations of end-of-life cognitive impairment with any one or any combination of five distinct NC. Assess impairment prevalence among subjects having natural resistance to each type of NC. METHODS: Brains from 1,040 autopsied participants of the Honolulu-Asia Study, the Nun Study, and the 90 + Study were examined for NC of AD, Lewy body dementia, microvascular brain injury, hippocampal sclerosis, and limbic predominate TDP-43 encephalopathy. Associations with impairment were assessed for each NC and for NC polymorbidity (variable combinations of 2-5 concurrent NC). RESULTS: Among 387 autopsied decedents with severe cognitive impairment, 20.4% had only AD lesions (ADNC), 25.3% had ADNC plus 1 other NC, 11.1% had ADNC plus 2 or more other NC, 28.7% had no ADNC but 1-4 other NC, and 14.5% had no/negligible NC. Combinations of any two, three, or four NC were highly frequent among the impaired. Natural resistance to ADNC or any other single NC had a modest impact on overall cohort impairment levels. CONCLUSION: Polymorbidity involving 1-5 types of concurrent NC is a dominant neuropathologic feature of AD and related dementias. This represents a daunting challenge to future prevention and could explain failures of prior preventive intervention trials and of efforts to identify risk factors.

Characterization of hippocampal sclerosis of aging and its association with other neuropathologic changes and cognitive deficits in the oldest-old.

Hippocampal sclerosis of aging (HS-A) is a common age-related neuropathological lesion characterized by neuronal loss and astrogliosis in subiculum and CA1 subfield of hippocampus. HS-A is associated with cognitive decline that mimics Alzheimer's disease. Pathological diagnosis of HS-A is traditionally binary based on presence/absence of the lesion. We compared this traditional measure against our novel quantitative measure for studying the relationship between HS-A and other neuropathologies and cognitive impairment. We included 409 participants from The 90+ study with neuropathological examination and longitudinal neuropsychological assessments. In those with HS-A, we examined digitized H&E and LFB stained hippocampal slides. The length of HS-A in each subfield of hippocampus and subiculum, each further divided into three subregions, was measured using Aperio eSlide Manager. For each subregion, the proportion affected by HS-A was calculated. Using regression models, both traditional/binary and quantitative measures were used to study the relationship between HS-A and other neuropathological changes and cognitive outcomes. HS-A was present in 48 (12%) of participants and was always focal, primarily affecting CA1 (73%), followed by subiculum (9%); overlapping pathology (subiculum and CA1) affected 18% of individuals. HS-A was more common in the left (82%) than the right (25%) hemisphere and was bilateral in 7% of participants. HS-A traditional/binary assessment was associated with limbic-predominant age-related TDP-43 encephalopathy (LATE-NC; OR = 3.45, p < 0.001) and aging-related tau astrogliopathy (ARTAG; OR = 2.72, p = 0.008). In contrast, our quantitative approach showed associations between the proportion of HS-A (CA1/subiculum/combined) and LATE-NC (p = 0.001) and arteriolosclerosis (p = 0.005). While traditional binary assessment of HS-A was associated with impaired memory (OR = 2.60, p = 0.007), calculations (OR = 2.16, p = 0.027), and orientation (OR = 3.56, p < 0.001), our quantitative approach revealed additional associations with impairments in language (OR = 1.33, p = 0.018) and visuospatial domains (OR = 1.37, p = 0.006). Our novel quantitative method revealed associations between HS-A and vascular pathologies and impairment in cognitive domains that were not detected using traditional/binary measures.

Pragmatic approaches to handling practice effects in longitudinal cognitive aging research.

INTRODUCTION: The challenge of accounting for practice effects (PEs) when modeling cognitive change was amplified by the COVID-19 pandemic, which introduced period and mode effects that may bias the estimation of cognitive trajectory. METHODS: In three Kaiser Permanente Northern California prospective cohorts, we compared predicted cognitive trajectories and the association of grip strength with cognitive decline using three approaches: (1) no acknowledgment of PE, (2) inclusion of a wave indicator, and (3) constraining PE based on a preliminary model (APM) fit using a subset of the data. RESULTS: APM-based correction for PEs based on balanced, pre-pandemic data, and with current age as the timescale produced the smallest discrepancy between within-person and between-person estimated age effects. Estimated associations between grip strength and cognitive decline were not sensitive to the approach used. DISCUSSION: Constraining PEs based on a preliminary model is a flexible, pragmatic approach allowing for meaningful interpretation of cognitive change. HIGHLIGHTS: The magnitude of practice effects (PEs) varied widely by study. When PEs were present, the three PE approaches resulted in divergent estimated age-related cognitive trajectories. Estimated age-related cognitive trajectories were sometimes implausible in models that did not account for PEs. The associations between grip strength and cognitive decline did not differ by the PE approach used. Constraining PEs based on estimates from a preliminary model allows for a meaningful interpretation of cognitive change.

Superior Global Cognition in Oldest-Old Is Associated with Resistance to Neurodegenerative Pathologies: Results from The 90+ Study.

BACKGROUND: Some oldest-old individuals can maintain superior cognition despite advanced age. Little is known about the neuropathological changes in the brains of oldest-old superior cognitive performers. OBJECTIVE: Our objective was to examine the associations between Alzheimer's disease (AD) and non-AD neuropathologic features in relation to superior cognitive performance in oldest-old individuals. METHODS: We analyzed brain autopsy data from 102 participants with normal cognition from The 90+ Study. Superior global cognitive performers (SGCP) were defined as having Mini-Mental State Examination (MMSE) score ≥28 in the last visit 12 to 2 months before death. To examine the associations between individual and multiple comorbid neuropathologic features with SGCP status we used multiple logistic regression models adjusting for age, sex, and education. RESULTS: Alzheimer's disease neuropathological change (ADNC) and low levels of vascular pathologic change were not associated with superior cognition. In contrast, participants with limbic (OR = 8.37; 95% CI: 1.48-47.44) and neocortical (OR = 10.80;95% CI: 1.03-113.82) Lewy body disease (LBD), or with hippocampal sclerosis (HS) (OR = 5.28; 95% CI: 1.10-25.47) were more likely to be non-SGCP. High total burden of multiple comorbid neuropathologic features was associated with a lower likelihood of being SGCP. CONCLUSION: Oldest-old superior cognitive performers were resilient to ADNC and low levels of vascular pathologic change and were resistant to non-AD neurodegenerative changes and multiple comorbid neuropathologic features. Understanding the factors underlying the ability of superior cognitive performers to resist these changes might provide useful insights on maintenance of superior cognition despite advanced age.

Assessing cognitive impairment in an ethnically diverse cohort of oldest-old: the life after 90 study.

BACKGROUND: Though dementia rates vary by racial or ethnic groups, it is unknown if these disparities remain among those aged 90 or older. AIMS: To test this hypothesis, we used baseline clinical evaluation of 541 ethnically and racially diverse individuals participating in the LifeAfter90 Study to assess how associations between core demographic characteristics and measures of physical and cognitive performance differ across the racial/ethnic groups. METHODS: Participants in this study were long-term non-demented members of Kaiser Permanente Northern California. They were clinically evaluated and diagnosed with normal or impaired cognition (mild cognitive impairment and dementia) through an in-person comprehensive clinical assessment consisting of a detailed medical history, physical and neurological examination, functional, and cognitive tests. RESULTS: The average age at enrollment was 93.0 ± 2.6 years, 62.4% female and 34.2% non-Hispanic White. At initial evaluation 301 participants had normal cognition and 165 had mild cognitive impairment (MCI) and despite screening, 69 participants were determined to have dementia. Age, education, 3MS, FAQ and CDR scores were significantly associated with cognitive impairment (normal versus MCI and dementia), but not gender. There was a significant univariate association between race/ethnicity and cognitive impairment (p < 0.02) being highest among Black (57.4%) and lowest among Asian (32.7%) individuals. After adjustment for age, gender, and education, however, prevalence of cognitive impairment was not influenced by race or ethnicity. CONCLUSION: Our results confirm the ability to reliably assess clinical diagnosis in a diverse sample of very old individuals.

Alzheimer's Disease Neuropathologic Change and Vitamin Supplement Use Decades Earlier: The 90+ Study.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia. AD neuropathologic change (ADNC) likely begins decades before clinical manifestations. One mechanism implicated in AD is oxidative stress. We explored the potential association of ADNC with antioxidant vitamin supplements taken about 30 years before death. METHODS: The 264 brain-autopsied participants were part of The 90+ Study, a longitudinal study of aging among people aged 90+ years, and originally members of the Leisure World Cohort Study, a population-based health study established in the 1980s. Intake of supplemental vitamins A, C, and E was collected by the Leisure World Cohort Study about 30 years before ADNC assessment. Odds ratios of ADNC (intermediate/high vs. none/low) for vitamin intake were estimated using logistic regression. RESULTS: The adjusted odds ratio (95% CI) of ADNC was 0.52 (0.29-0.92) for vitamin E supplements and 0.51 (0.27-0.93) for vitamin C supplements. Supplemental vitamin E intake was the first variable, after education, to enter the stepwise model. Intake of vitamin A or C did not improve the model fit. CONCLUSIONS: The observed association of ADNC and supplemental vitamin E intake decades earlier suggests a beneficial effect and supports further investigation into a nutritional approach to preventing AD with vitamin supplementation.

Study of neuropathological changes and dementia in 100 centenarians in The 90+ Study.

INTRODUCTION: The association between neuropathological changes and dementia among centenarians and nonagenarians remains unclear. METHODS: We examined brain tissue from 100 centenarians and 297 nonagenarians from The 90+ Study, a community-based longitudinal study of aging. We determined the prevalence of 10 neuropathological changes and compared their associations with dementia and cognitive performance between centenarians and nonagenarians. RESULTS: A total of 59% of centenarians and 47% of nonagenarians had at least four neuropathological changes. In centenarians, neuropathological changes were associated with higher odds of dementia and, compared to nonagenarians, the odds were not attenuated. For each additional neuropathological change, the Mini-Mental State Examination score was lower by 2 points for both groups. DISCUSSION: Neuropathological changes continue to be strongly related to dementia in centenarians, highlighting the importance of slowing or preventing the development of multiple neuropathological changes in the aging brain to maintain cognitive health. HIGHLIGHTS: Individual and multiple neuropathological changes are frequent in centenarians. These neuropathological changes are strongly associated with dementia. There is no attenuation of this association with age.

LATE-NC staging in routine neuropathologic diagnosis: an update.

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

Reduced structural connectivity of the medial temporal lobe including the perforant path is associated with aging and verbal memory impairment.

The perforant path, the white matter bundle connecting the entorhinal cortex (ERC) with the hippocampal formation deteriorates with age-related cognitive decline. Previous investigations using diffusion-weighted MRI to quantify perforant path integrity in-vivo have been limited due to image resolution or have quantified the perforant path using methods susceptible to partial volume effects such as the tensor model and without consideration of its 3-dimensional morphology. In this investigation, we use quantitative-anisotropy informed tractography derived from ultra-high resolution diffusion imaging (ZOOMit) to investigate structural connectivity of the perforant path and other medial temporal lobe (MTL) pathways in older adults (63 to 98 years old, n = 51). We show that graph density within the MTL declines with age and is associated with lower delayed recall performance. We also show that older age and poorer delayed recall are associated with reduced streamlines connecting the ERC and dentate gyrus of the hippocampus (the putative perforant path). This work suggest that intra-MTL connectivity may new candidate biomarkers for age-related cognitive decline.

Posterior white matter hyperintensities are associated with reduced medial temporal lobe subregional integrity and long-term memory in older adults.

White matter hyperintensities are a marker of small vessel cerebrovascular disease that are strongly related to cognition in older adults. Similarly, medial temporal lobe atrophy is well-documented in aging and Alzheimer's disease and is associated with memory decline. Here, we assessed the relationship between lobar white matter hyperintensities, medial temporal lobe subregional volumes, and hippocampal memory in older adults. We collected MRI scans in a sample of 139 older adults without dementia (88 females, mean age (SD) = 76.95 (10.61)). Participants were administered the Rey Auditory Verbal Learning Test (RAVLT). Regression analyses tested for associations among medial temporal lobe subregional volumes, regional white matter hyperintensities and memory, while adjusting for age, sex, and education and correcting for multiple comparisons. Increased occipital white matter hyperintensities were related to worse RAVLT delayed recall performance, and to reduced CA1, dentate gyrus, perirhinal cortex (Brodmann area 36), and parahippocampal cortex volumes. These medial temporal lobe subregional volumes were related to delayed recall performance. The association of occipital white matter hyperintensities with delayed recall performance was fully mediated statistically only by perirhinal cortex volume. These results suggest that white matter hyperintensities may be associated with memory decline through their impact on medial temporal lobe atrophy. These findings provide new insights into the role of vascular pathologies in memory loss in older adults and suggest that future studies should further examine the neural mechanisms of these relationships in longitudinal samples.